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At least 19 recordsLinked to original sources
PubMed1995

Antimanic drugs stabilize hamster circadian rhythms.

The circadian wheel-running rhythm of golden hamsters was monitored during chronic oral treatment with four mood-stabilizing drugs in doses relevant for treatment of manic-depressive disorder. Carbamazepine and verapamil shortened the duration of locomotor activity and improved the stability of the pattern of running activity. At comparable doses, valproate had no clear effect on any rhythm variable tested. None of these drugs consistently altered the phase of light-synchronized running rhythms or the period of the rhythm in constant darkness. The results are compared to data showing that lithium, which delays entrained phase and lengthens circadian period in hamsters, also shortens activity duration and increases the stability of wheel-running rhythms. Stabilization of circadian rhythms may be a key action of clinically effective mood-stabilizing drugs.

Animals↗
PubMed2007

Compressed oxygen in drug stability experiments.

A drug stability experiment accelerated by compressed oxygen was established. The stability of 10% ascorbic acid solution as a model was studied and the kinetic parameters were obtained with the newly established experimental method. Because ascorbic acid degrades under both anaerobic and aerobic conditions, the total rate constant k(total) can be expressed as: k(total)=k(anaerobic) + k(aerobic), where k(anaerobic) and k(aerobic) are the rate constants of anaerobic and aerobic degradations, respectively. The k(anaerobic) can be expressed as k(anaerobic) = A(anaerobic) x exp(-E(a,anaerobic)/RT) according to Arrhenius equation, and the k(aerobic) was found to be k(aerobic) = A(aerobic) x exp(-E(a,aerobic)/RT) x p(O2) in our study.

Ascorbic Acid↗
PubMed2006

Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate.

Mood stabilizing drugs lithium and valproate are the most commonly used treatments for bipolar disorder. Previous studies in our laboratory indicate that chronic treatment with lithium and valproate inhibits oxidative damage in primary cultured rat cerebral cortical cells. Glutathione, as the major antioxidant in the brain, plays a key role in defending against oxidative damage. The purpose of this study was to determine the role of glutathione in the neuroprotective effects of lithium and valproate against oxidative damage. We found that chronic treatment with lithium and valproate inhibited reactive oxygen metabolite H(2)O(2)-induced cell death in primary cultured rat cerebral cortical cells, while buthionine sulfoximine, an inhibitor of glutathione rate-limiting synthesis enzyme glutamate-cysteine ligase, reduced the neuroprotective effect of lithium and valproate against H(2)O(2)-induced cell death. Further, we found that chronic treatment with lithium and valproate increased glutathione levels in primary cultured rat cerebral cortical cells and that the effects of lithium and valproate on glutathione levels were dose-dependent in human neuroblastoma SH-SY5Y cells. Chronic treatment with lithium and valproate also increased the expression of glutamate-cysteine ligase in both rat cerebral cortical cells and SH-SY5Y cells. In addition, chronic treatment with other mood stabilizing drugs lamotrigine and carbamazepine, but not antidepressants desipramine and fluoxetine, increased both glutathione levels and the expression of glutamate-cysteine ligase in SH-SY5Y cells. These results suggest that glutathione plays an important role in the neuroprotective effects of lithium and valproate, and that glutathione may be a common target for mood stabilizing drugs.

Animals↗
PubMed1989

Drug stability testing by monitoring drug and degradate levels by liquid chromatography.

A cephalosporin antibiotic and its primary degradation product can be separated by a mixed retention mechanism using an ion exchange column and a mobile phase containing acetonitrile and aqueous sodium phosphate. Assay ruggedness, specificity, linearity of response, and standard-sample stability are evaluated and found to be adequate for the desired application. Drug degradation at room temperature in formulations containing citrate and dextrose is found to be roughly first order; fit of the first order rate expression model is better when gain in degradate levels is used as opposed to the direct measurement of drug loss, especially when the magnitude of drug loss is small. The greater accuracy of projections based on the measurement of degradate gain is related to the effect of the imprecision of the analytical measurement on the accuracy of the model.

Chromatography, High Pressure Liquid↗
PubMed1987

Statistical evaluation of nonisothermal prediction of drug stability.

Nonisothermal prediction of drug stability based on direct nonlinear estimation of the shelf-life was compared with the isothermal approach. The reliability of the statistics for the estimates of the shelf-life (the time period required for a drug to degrade to 90% remaining at 25 degrees C) and activation energy obtained by the two methods was evaluated by the Monte Carlo method of computer simulations. The accuracy and precision of the estimates obtained by the nonisothermal method depended largely on the experimental conditions, such as experimental periods, sampling time, and temperature rise programs. The uncertainty of the estimates was determined mainly by the extents of drug degradation and temperature change achieved during the experiment. The nonisothermal method needed suitable experimental designs and precise assay methods of drug contents to provide reliable parameter estimates.

Computers↗
PubMed1999

Mood-stabilizing drugs in depression.

Mood-stabilizing drugs including lithium, anticonvulsants, and antipsychotics have established effects in the management of bipolar disorder, especially in mania. However, these drugs also have been shown to be effective in depressed patients. For example, lithium is well established as an effective augmenting strategy with tricyclic antidepressants in refractory depression. This article will review a variety of effects of mood-stabilizing drugs in bipolar and unipolar depressed patients, which will include acute treatment, prevention of relapse and recurrence, and the management of refractory patients. The effects of antipsychotics (especially atypicals) and new research directions also will be reviewed.

Acute Disease↗
PubMed2005

Programmed humidifying in drug stability experiments.

The stability of penicillin potassium, as a solid state model, was investigated by a programmed humidity and temperature controlled method. An optimization calculational approach to data handling is suggested. The stability of drugs which are unstable to both heat and moisture could be studied by a single pair of experiments, one with programmed humidity control and one non-isothermal, rather than many standard isothermal studies, each at constant relative humidity. The controlling system, based on a pocket computer, was found to be accurate and reliable. The results indicated that the kinetic parameters obtained were comparable to those from isothermal studies.

Drug Stability↗
PubMed1986

The role of beta blocking agents as adjunct therapy to membrane stabilizing drugs in malignant ventricular arrhythmia.

Antiarrhythmic drugs are often either partially or totally ineffective for the suppression of ventricular arrhythmias in a given patient. Drug combinations afford an additional therapeutic option. We report the role of beta-blocking agents as adjunct therapy to membrane stabilizing drugs in the management of patients with malignant ventricular arrhythmias. The study group included 54 patients who were evaluated by 24-hour ambulatory monitoring and symptom-limited exercise testing. Patients underwent control studies without antiarrhythmic drugs, were evaluated on membrane stabilizing drugs and beta blocking agents separately, and were then tested on combination therapy. The combination of a beta-blocking agent and a membrane stabilizing drug abolished ventricular tachycardia and couplets in 83% and 86% of exercise tests in patients with this arrhythmia present during therapy with membrane drugs alone (p less than 0.01). The addition of a beta blocker to a membrane drug, as evaluated by ambulatory monitoring, resulted in an abolition of ventricular tachycardia and couplets in 43% and 20% of studies (p less than 0.05). Ventricular premature beat frequency was reduced by more than 50% in 65% of exercise tests and in 52% of monitoring studies (p less than 0.05). In this population, beta-blocking agents failed to reduce ventricular arrhythmias when used alone. Thus the addition of a beta blocker to a membrane stabilizing drug significantly enhances the suppression of ventricular arrhythmia, especially when assessed by exercise testing. This results from synergistic drug effects of the combination rather than from the effect of the individual drugs.

Adrenergic beta-Antagonists↗
PubMed2002

Pharmacogenetics of antidepressant and mood-stabilizing drugs: a review of candidate-gene studies and future research directions.

Heterogeneity of clinical response to antidepressant and mood-stabilizing drugs and susceptibility to adverse effects are major clinical problems. It is reasonable to suggest a genetic contribution to these inter-individual differences. Thus, pharmacogenetic approaches could provide the clinician with tools to individualize pharmacotherapy. In this paper, published reports that address the genetic basis of response to antidepressant drugs and mood-stabilizing drugs are selectively reviewed. There is substantial support for the assumption that genetic factors play a role in response to lithium and a degree of support for a role of such factors in response to antidepressants. Based on a Medline search and access to papers accepted but not yet published, studies on the role of specific candidate genes are comprehensively evaluated. A number of studies from different groups point to a role for polymorphism of the serotonin transporter gene in the therapeutic response to specific serotonin reuptake inhibitors. There are reports of other candidate genes, particularly in the serotonergic system, but these have still to be replicated. There is little evidence thus far that points to a role for specific candidate genes in response to mood-stabilizing drugs. Future research directions including the selection of relevant candidate genes, pivotal issues in the design of studies and high throughput methods of analysis are discussed in the light of the findings. Although pharmacogenetic approaches have great potential in the treatment of major depression and bipolar disorder, substantial further research is needed. Careful attention needs to be paid to research design issues and potential confounding factors such as population stratification. High throughput, genome-wide approaches could greatly accelerate the acquisition of relevant data but their success is dependent on the availability of appropriate clinical samples.

Affect↗
PubMed2005

Mood-stabilizing drugs: are their neuroprotective aspects clinically relevant?

The possibility that there may be subtypes of bipolar disorder and the slow progress in understanding the therapeutic mechanism for approved mood-stabilizing drugs make the challenges of intelligent drug design seem daunting. Nonetheless, the numerous shortcomings in current pharmaco-therapy underscore the need to develop novel therapies. There are significant problems with currently approved mood-stabilizing drugs: 1. Up to 40% of patients fail to respond to monotherapy with either lithium or valproic acid. 2. Common use of polypharmacotherapy increases the side effects associated with treatment. 3. Treatment must continue for weeks to months for therapeutic effects to be greater than placebo. 4. Up to 60% of patients will discontinue therapy, which is somewhat attributable to unwanted side effects. Thus, it is critical that new medications without these problems be developed for bipolar disorder. The hypothesis that mood-stabilizing drugs are neuroprotective is an important first step in new drug development. To determine if the clinical efficacy of mood-stabilizing drugs is dependent on the neuroprotective or neurogenic properties of these medications, greater strides need to be made in relating findings from cell culture and animal models to human imaging and pathology. Mounting evidence supports the neuroprotective and neurogenic properties of lithium and valproic acid ina variety of cell-culture models. It is important for clinical, biochemical, and in vitro differences between these medications to be examined, not ignored,because these differences may reveal critical distinctions between the neural mechanisms of these drugs. Continuation of the in vitro work will aid in the understanding of the mechanism by which these drugs are neuroprotective,but such studies do not advance the understanding of whether these effects are critical for the clinical efficacy of these medications. In attempting to understand the in vivo effects of these medications, a variety of evidence supports the neuroprotective and neurogenic aspects of lithium and valproic acid in healthy rodents and animal models of gross brain insult. More work needs to be done to assess whether these effects occur in animal models for bipolar disorder. The proof of principle for supporting the claim that the neuroprotective or neurogenic properties are important clinically will come from longitudinal clinical studies that compare brain morphology and function before and during treatment. If enough evidence supports the hypothesis that the neuroprotective and neurogenic properties of mood-stabilizing drugs are important for their clinical efficacy, new medications that are more efficacious and have fewer side effects will be designed based on this discovery.

Affect↗
PubMed1990

Applications of oxygen polarography to drug stability testing and formulation development: solution-phase oxidation of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors.

The kinetics of oxidation of the HMG-CoA reductase inhibitors lovastatin, simvastatin, L-157,012, and L-647,318 were studied in an aqueous surfactant solution. A thermally labile free radical initiator was used to attain measurable reaction rates at 40 degrees C and rate constants were determined by measuring oxygen consumption using an oxygen electrode. The stability of the drugs was found to increase in the order lovastatin = simvastatin less than L-157,012 less than L-647,318. The addition of butylated hydroxyanisole (BHA) was found to stabilize the drugs. For the oxidation of lovastatin, the effectiveness of antioxidants increased in the order propyl gallate less than BHA less than alpha-tocopherol. It is concluded that the stability of oxidizable drugs can be rapidly and conveniently assessed by the techniques described herein.

Antioxidants↗
PubMed1975

Inhibition of induced pinocytosis in Amoeba proteus by membrane stabilizing drugs.

The effect of membrane stabilizing drugs on cation induced pinocytosis was studied in Amoeba proteus. Initially the presence of local anesthetic drugs during a pinocytosis cycle had a stimulating effect on channel formation, however, the capacity to develop pinocytotic channels was reversibly inhibited after a period of treatment with these drugs. Imipramine, vinblastine and the phenothiazines had effects similar to local anaesthetics. The local anesthetics inhibited pinocytosis in the following order: dibucaine greater than tetracaine greater than bupivacaine greater than lidocaine greater than procaine, and the phenothiazines: thioridazine greater than prochlorperazine greater chlorpromazine greater than prometazine. Pinocytosis, when induced by Na+ or tris, was more affected by the drugs and by calcium binding agents than pinocytosis induced by K+. After pretreatment with inhibitory concentration of dibucaine (3 x 10(-4) M) the depolarization of the membrane and the conductance increase during pinocytosis were normal, while the increase of oxygen uptake during the pincoytosis cycle was abolished. Addition of Ca++ before, during or after dibucaine treatment decreased the effect of the drug. Conversely, in dibucaine-treated cells, cation induced pinocytosis was less inhibited by Ca++ than pinocytosis in normal cells. Addition of EGTA to the inducing solutions potentiated the inhibitory effect of the drug. It is suggested that these drugs release Ca++ from the cell surface and at higher concentration or after prolonged incubation time interfere with a Ca++ mechanism which couples the membrane and contractile systems in the cytoplasm.

Amoeba↗
PubMed1994

High-performance liquid chromatography for small-scale studies of drug stability.

The fundamentals of high-performance liquid chromatography (HPLC), as applied in small-scale studies of drug stability, are presented. Chromatography is the separation of a complex mixture into its individual compounds through partitioning between a mobile phase and a stationary phase. A high-performance liquid chromatograph consists of mobile-phase reservoirs, pumps, a mixer to mix the solvents, a valve into which the sample is injected, a guard column, a column containing the stationary phase, a detector, and a recorder. Once compounds have been separated in the column, they pass into the detector, where an electronic signal corresponding to the amount of compound present is recorded as a peak in a chromatogram. The most common detection method is ultraviolet and visible light spectroscopy. Key concepts in HPLC theory are retention time, the time from injection of the sample to detection of a peak; capacity factor, a measure of retention corrected for the elution of an unretained compound; resolution, a measure of how well two peaks are separated; the selectivity of the method; efficiency, or resolving power; and the degree of symmetry of the peaks produced. Most HPLC separations are performed in the reverse-phase mode, which involves a nonpolar stationary phase and a largely polar mobile phase. Other modes are normal phase, ion exchange, and size exclusion. Before a drug stability study is carried out, an HPLC method must be developed that suits the needs of the proposed experiment. A thorough literature search is essential. Literature procedures serve as useful starting points but may require a great deal of manipulation. After the HPLC separation has been performed, it is necessary to validate the method used. It must be proved that the method is stability indicating, that the chromatographic standards were properly prepared, that the standard curve is acceptable, and that the method is both precise and accurate. Pharmacists who ensure that reliable, reproducible HPLC methods are used throughout studies of drug stability will obtain sound data that may be of great value in pharmacy practice.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

[Drug stability].

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Drug Stability↗
PubMed2005

Mood stabilizing drug lithium increases expression of endoplasmic reticulum stress proteins in primary cultured rat cerebral cortical cells.

The mood stabilizing drug lithium is a highly effective treatment for bipolar disorder. Previous studies in our laboratory found that chronic treatment with the mood stabilizing drug valproate in rat brain increased the expression of endoplasmic reticulum (ER) stress proteins GRP78, GRP94 and calreticulin. We report here that in primary cultured rat cerebral cortical cells, expression of GRP78, GRP94 and calreticulin are increased not only by valproate, but also by lithium after chronic treatment for 1 week at therapeutically relevant concentrations. However, two other mood stabilizing drugs carbamazepine and lamotrigine had no effect on expression of GRP78, GRP94 or calreticulin. Chronic treatment with lithium for 1 week increased both mRNA and protein levels of ER stress proteins. In contrast to a classic GRP78 inducer thapsigargin, an inhibitor of the ER Ca2+ -ATPase, chronic treatment with lithium or valproate for 1 week modestly increased GRP78 expression in neuronal cells, had no effect on basal intracellular free Ca2+ concentration and does not induce cell death. These results indicate that lithium and valproate may increase expression of GRP78, GRP94 and calreticulin in primary cultured rat cerebral cortical cells without causing cell damage. These results also suggest that the mechanism of GRP78 increase induced by lithium and valproate may be different from that of thapsigargin.

Animals↗